* Chromophobe renal cell carcinoma (CRCC) is a distinct subtype of
renal cell carcinoma (RCC) that is well known for its relatively good
prognosis. Sarcomatoid transformation in this tumor, although rare, has
been well documented in the literature and, as in other types of RCC,
carries an ominous prognosis for the patient. The finding of
heterologous elements in the sarcomatoid component of CRCC is an
extraordinary event, which has been reported in only 2 previous cases.
Here, we present the third such case, occurring in the left kidney of a
previously healthy 63-year-old woman. The nephrectomy specimen showed
CRCC with extensive sarcomatoid changes displaying heterologous elements
in the form of chondrosarcomatous and osteosarcomatous differentiation.
As in other sarcomatoid RCCs, this tumor behaves aggressively, with
frequent distant metastases. It is important to recognize the
sarcomatoid component in these tumors because of its consequential
adverse prognosis for the patient.

Chromophobe renal cell carcinoma (CRCC) is a distinct subtype of
renal neoplasm characterized by the presence of polygonal cells with
well-defined borders and clear or eosinophilic cytoplasm with
perinuclear clearing, which gives them a distinct plant cell-like
appearance. This neoplasm is well known to behave less aggressively than
other renal cell carcinomas (RCCs). (1) In past years, there have been
reports suggesting that CRCC may indeed be more prone to undergo
sarcomatoid dedifferentiation than other RCCs. (2) When
dedifferentiation occurs, the presence of heterologous elements in the
sarcomatoid component is a rather uncommon event. (3)

Here, we present one such case in which the tumor showed CRCC with
extensive sarcomatoid changes containing heterologous elements in the
forms of chondrosarcomatous and osteosarcomatous differentiation.

CLINICAL HISTORY

The patient is a 63-year-old previously healthy woman who presented
in August 2006 complaining of episodes of nausea and mild left flank
pain that started 2 months prior to her first medical visit. A computed
tomography scan was obtained, which showed an upper pole left renal mass
with renal vein involvement. Under the clinical diagnosis of RCC, she
underwent a left radical nephrectomy with a periaortic lymph node
dissection, as well as a left adrenalectomy and splenectomy. Three
months after surgery, the patient was found to have multiple pulmonary
nodules, along with hepatic and bone (sacral) metastases. The patient
was treated with radiotherapy and chemotherapy for her distant
metastatic disease. She is currently alive with disease 10 months after
the diagnosis.

PATHOLOGY

Macroscopic Features

A radical nephrectomy specimen consisted of left kidney surrounded
by perinephric adipose tissue and Gerota fascia (592 g), with the kidney
alone measuring 12.0 x 8.0 x 6.0 cm. A 6.0 x 6.0 x 5.5 cm mass occupied
most of the upper pole and displayed a gray-tan to yellow-tan tumor with
areas of necrosis (40% of tumor), fibrosis, and calcification. The tumor
invaded the overlying perinephric adipose tissue posteriorly. It also
invaded the renal vein, forming an embolus (4.5 x 2.1 x 2.0 cm), with
obstruction and dilatation of the vessel extending to within less than
0.1 cm of the margin. The tumor also appeared to involve the renal
pelvis. Grossly, 1 of 12 submitted lymph nodes showed tumor metastasis.
The adrenal gland was normal and free of tumor.

Microscopic Features

The sections of kidney showed a biphasic, malignant epithelial and
sarcomatoid neoplasm, with CRCC as the carcinomatous element and a
high-grade pleomorphic sarcoma as the sarcomatoid component (Figure 1).
The latter displayed areas of osteosarcoma and chondrosarcoma (Figure
2). The sarcomatous element represented about 70% of the tumor, with 5%
composed of osteosarcomatous and chondrosarcomatous components. Areas of
calcification were seen at the periphery of the tumor, and there was
invasion into the perinephric fat and renal vein. One of the 12 lymph
nodes showed metastatic disease exclusively composed of sarcomatoid
component without the CRCC element. Tumor necrosis was about 40% of the
total tumor volume. The adrenal gland and spleen were both free of tumor
(T3bN1MX).

AE1/AE3 stain showed diffuse positivity, but there was only focal
positivity for cytokeratin 7 in the epithelial component.
Kidney-specific cadherin was also diffusely positive in the epithelial
component (Figure 4), whereas vimentin, SMA, and c-kit were negative. In
the sarcomatoid component, diffuse vimentin positivity (Figure 5) and
focal SMA positivity were observed, whereas other markers, as well as
Hale colloidal iron stain, were negative. Stain for MIB-1 showed strong
positivity in more than 30% of the sarcomatoid cells, but only 10% in
the epithelial component (Figure 6). Stain for p53 was negative in both
the epithelial and sarcomatoid components.

COMMENT

Chromophobe renal cell carcinoma is an infrequent subtype of RCC,
representing about 5.9% of total RCCs. (4) The age of presentation may
have a wide range, but it tends to occur in patients between 20 and 40
years old, which is a younger age presentation than that seen in other
RCC subtypes. (5) Chromophobe renal cell carcinoma is generally detected
incidentally, but when symptomatic, it can present with hematuria, flank
pain, and/or a mass. (6) Radiologically, CRCC presents as a
well-defined, homogeneously echoic, and hypovascular mass. (5)
Clinically, CRCC patients have been reported to have a more favorable
prognosis than that associated with other histologic subtypes of RCC.
(2)

[FIGURE 3 OMITTED]

[FIGURE 4 OMITTED]

[FIGURE 5 OMITTED]

[FIGURE 6 OMITTED]

In general, the incidence of sarcomatoid transformation in RCC is
around 5%. (3) This process is thought to result from dedifferentiation
of the epithelial component, and so the sarcomatoid cells are expected
to show the original genomic pattern of the "parent" cells.
X-chromosome inactivation analysis has confirmed this hypothesis by
showing different patterns of allelic loss in multiple chromosomal
regions, indicating divergence during the clonal evolution of RCC. (7)
The sarcomatoid dedifferentiation in any type of RCC carries a poor
prognosis for most patients, (4) and most of them present with advanced
stage at initial diagnosis. The disease-specific survival rate of
sarcomatoid RCC is decreased compared with RCC without sarcomatoid
change. The amount of sarcomatoid component (equal to or more than 50%)
and lymphovascular invasion are also associated with decreased survival.
(8)

Heterologous sarcomatoid transformation also has been reported in
other histologic subtypes of sarcomatoid RCC, and conventional RCC is
the main type of tumor to undergo this heterologous transformation. Its
incidence is about 1.5% of all sarcomatoid RCCs.

Akhtar et al (2) in 1997 first documented the sarcomatoid
transformation in CRCC, and thereafter additional reports have been
published. (9-14) The incidence of sarcomatoid transformation observed
in a large series of CRCC was 8.7%.3 Akhtar el al (2) suggested that the
sarcomatoid development in CRCC might be associated with its peculiar
genetic profile, which would make the cells prone to hyperploidization.
This observation has been extensively studied by Brunelli et al, (15)
who found that both the epithelial and sarcomatoid elements in a CRCC
show different genetic abnormalities than those considered a
"hallmark" of CRCC. The sarcomatoid CRCC shows multiple gains
of chromosomes 1, 2, 6, 10, and 17. (15)

In most cases, the dedifferentiated elements, referred to as
sarcomatoid components, are homologous in type, with a malignant fibrous
histiocytoma-like or fibrosarcoma-like pattern. However, there are only
2 previously reported patients whose tumors disclosed heterologous
differentiation of the sarcomatoid component. The first case, published
in 1999 by Hes et al, (13) occurred in a 74-year-old patient with a
sarcomatoid CRCC that exhibited osteosarcomatous, chondrosarcomatous,
and rhabdomyosarcomatous elements. The second case, reported in 2002 by
Itoh et al, (12) was a 74-year-old man who had a CRCC with
osteosarcomatous and chondrosarcomatous differentiation. The Table
summarizes the major clinical and pathologic features of the previously
reported cases, including the current case.

Chromophobe renal cell carcinoma is diffusely positive for Hale
colloidal iron stain and usually expresses E-cadherin or kidney-specific
cadherin, pancytokeratin (AE1/ AE3), and CK7, but is negative for
vimentin, c-kit, and SMA. The sarcomatoid component is positive for
vimentin and negative for cytokeratin, colloidal iron, and cadherin.
(14) Our case revealed typical histochemical and immunohistochemical
findings in the carcinomatous component, with AE1/AE3, kidney-specific
cadherin, and CK7 positivity, and negativity with vimentin, SMA, and
c-kit. In the sarcomatoid component, there was diffuse vimentin
positivity and focal SMA positivity and negativity for colloidal iron
stain as well as AE1/AE3, CK7, and kidney-specific cadherin. In
addition, stain for MIB-1 showed strong positivity in more than 30% of
the sarcomatoid cells, but only 10% in the epithelial component. Stain
for p53 was negative in both the epithelial and sarcomatoid components.

Most of the previously reported cases of sarcomatoid CRCC are in
concordance with the above-mentioned data. The mean age of presentation
in the sarcomatoid CRCCs was higher than that of the ordinary CRCCs;
sarcomatoid CRCCs were usually locally aggressive and patients presented
with metastatic disease at the time of diagnosis. In general, survival
of these patients was very short. As with any other type of RCC, these
tumors are highly resistant to chemotherapy.

The primary histologic subtype of RCC, whether it has homologous or
heterologous sarcomatoid components, is no longer significant to predict
outcome, since the stage (TNM) of the lesion appears to be the only risk
factor to predict outcome.

In the case of sarcomatoid CRCC, the situation is similar: the
usual 5-year disease-specific survival rate of CRCC that is close to
100% and the 5-year progression-free survival of 94%4 drop to the levels
comparable to those of other sarcomatoid RCCs.

It is very important to recognize CRCC as a distinct subtype of
renal neoplasm, so much as the diagnosis implies a favorable prognosis
to the patient. However, if sarcomatoid transformation develops, the
patient's prognosis is very poor.

We report a case of CRCC with heterologous sarcomatoid elements
with osteosarcomatous and chondrosarcomatous elements that is apparently
the third reported case of heterologous sarcomatoid CRCC.